This proposed K-23 grant resubmission will provide for the career development of a junior principal investigator who aims to become a leader in human immunodeficiency virus (HIV) clinical research with a focus on the central nervous system (CNS) involvement of HIV. The CNS complications of HIV continue to be a major source of morbidity and mortality. The prevalence of HIV-associated neurocognitive disorder (HAND) is increasing. The presence of HAND is a risk factor for work disability, poor quality of life, and mortality. The proposed research plan addresses three of the most important areas of HIV central nervous system (CNS) research: the possibility that certain antiretroviral medications differentially affect cognitive improvement in HAND, the role of specific cerebrospinal fluid (CSF) biomarkers as indicators of HAND activity, and the incompletely defined role of monocyte and lymphocyte activation in HIV neuropathogenesis. The proposed research is highly relevant to NIMH missions, which include the development of novel therapeutic approaches to mitigate the CNS complications of HIV. The research will take place in an urban HIV center where many of the patients have limited resources due to poverty and lack of medical insurance. Zidovudine is an antiretroviral medication that is now in generic form in the United States, is among the most effective antiretrovirals in penetrating the CNS, and is historically the best studied antiretrovirl for HIV-associated dementia. The investigator's primary hypothesis is that the addition of zidovudine in antiretroviral-nave subjects with HAND will result in significantly greater neurocognitive improvement and biomarkers over the course of 48 weeks. This will be tested in a small clinical study in which subjects will receive a standard of care antiretroviral regimen plu either zidovudine or placebo. If the study shows superior improvement in neurocognition and/or biomarkers for subjects randomized to zidovudine, the team will pursue larger studies of zidovudine addition for individuals with HAND. The secondary aims of the proposal pertain to the hypothesis that biomarkers are a reflection of HAND and that cytokines and peripheral immune activation independently contribute to HAND and may be targets for modification with future therapies. The research team aims to estimate normal CSF biomarker values based on an established large repository of samples. They have shown that certain biomarkers correlate with HAND severity and improve during treatment. One aim would be to test a composite score of eight biomarkers alongside standardized neuropsychological testing. If a promising correlation is demonstrated, the biomarker score would be tested in larger studies as a correlate of HAND. The research team has also demonstrated in previous work that CSF IFN-alpha levels inversely correlate with neuropsychological scores in subjects with HAND. They have also shown that in a mouse model of HIV encephalitis, treatment with IFN-alpha blockade was associated with a benefit in working memory and decreased pathological markers in the brain. The proposed clinical study will allow the team to build on these findings. The team hypothesizes that individuals with residual neurocognitive impairment despite effective antiretroviral therapy will have higher residual CSF IFN-alpha levels. This would form the basis for clinical studies of IFN-alpha modifying therapy that the research team has developed for individuals with HAND. Another secondary aim is to examine the role of peripheral monocyte and lymphocyte activation in HAND. It is clear that peripheral lymphocyte activation contributes to overall AIDS pathogenesis. However, it is not known if lymphocyte activation independently contributes to HAND. Current evidence suggests that peripheral monocyte activation represents one of the initial steps in the establishment of the HIV reservoir in the brain. However, it is unclear whether peripheral monocyte activation is more modifiable with certain antiretroviral medications. This study will examine whether subjects with HAND randomized to zidovudine, which has demonstrated antiretroviral activity within monocytes, have less peripheral monocyte activation. If the proposed study indicates that HAND severity is related to peripheral immune activation and that the beneficial effect of certain antiretroviral agents may be related to modification of immune activation, this would lead to future studies of therapies that directly target immune activation for the amelioration of HAND or as a means to interrupt the establishment of the HIV reservoir in the brain, which represents one of the barriers to HIV eradication. The principal investigator for this proposal has assembled a diverse mentoring team with experts from HIV clinical research, neurosciences, and HIV basic research. These mentors each bring important strengths to the multidisciplinary research plan and have agreed to meet regularly with the principal investigator in order to provide guidance in research and career development. The principal investigator has significant experience in HIV clinical care and research. In addition to his medical degree, he holds a masters degree in health sciences research. He is based at one of the largest centers for HIV care in the United States. As part of the research proposal, he will also receive formal coursework in neuro-HIV/AIDS research, clinical trials, neuropsychology, biostatistics, and the responsible conduct of research. He will regularly attend international HIV research meetings in which he will present his research. Overall, this career development project will allow the principal investigator to pursue the goal o becoming an established investigator and leader in HIV CNS research.